Remodelling of Skeletal Muscle During Iron Deficiency Anaemia and Recovery After Intravenous Iron Therapy

ABSTRACT Background The global prevalence of iron deficiency anaemia (IDA) is about 25% and even higher in women of reproductive age and children. IDA can impair skeletal muscle by disrupting oxygen utilization, energy production and contractile function. Haematological effects of intravenous (IV) iron therapy in IDA are well studied, but its impact on muscle and energy metabolism is less clear. We investigated the molecular and functional effects of IDA on skeletal muscle in a mouse model and C2C12 myotubes. The effects of different IV iron formulations on skeletal muscle were compared in iron deficient C2C12 myotubes, in IDA‐mice and patients with IDA. Methods Treatment effects of the IV iron formulations ferric carboxymaltose (FCM) and ferric derisomaltose (FDI) were studied in IDA mice by tail vein injection of 2‐mg iron. Analyses were carried out 7 days and 4 weeks post‐treatment. C2C12 myotubes were treated with desferrioxamine, followed by incubation with FCM or FDI before mitochondrial respiration, gene expression and metabolite profiles were analysed. Respiratory muscle function was investigated in adults with IDA treated with FCM or FDI as exploratory endpoint in a randomized clinical trial. Results In our mouse model IDA induced a trend towards impaired skeletal muscle function and a shift to anaerobic metabolism. Only treatment with FDI resulted in a significant increase in muscle type I and type IIb fibre cross‐sectional area when compared to IDA. FDI also induced earlier recovery of contractile protein expression and energy metabolism than FCM. Exploratory proteomic and metabolic analyses revealed that treatment with FDI might restore mitochondrial enzymes and reduce lactate accumulation after 7 days. In vitro, iron‐deficient C2C12 myotubes showed reduced mitochondrial respiration and increased glycolysis with partial recovery by both IV iron formulations. Two weeks after treatment of IDA in adults, FDI caused a significantly better improvement in maximal expiratory pressure than FCM (mean pressure difference between treatments 5.06 cmH 2 O, p = 0.013). This difference appeared unrelated to post‐treatment hypophosphatemia. Conclusions IDA shows a trend towards impaired skeletal muscle function through metabolic and structural remodelling in mice, which is restored with different kinetics by FDI and FCM. These findings are in accord with exploratory findings from a clinical study indicating better respiratory muscle recovery in FDI‐treated than FCM‐treated IDA patients. Cell culture experiments confirm the effects of IDA on impaired metabolism but did not show differential effects of FCM and FDI. Different tissue pharmacokinetics could explain the distinct in vivo response of both formulations.